The present invention is directed to ophthalmic compositions that include an anionic drug. The ophthalmic compositions are formulated so as to have sufficient antimicrobial activity to satisfy the preservation efficacy requirements of the United States Pharmacopeia (“USP”) and/or analogous guidelines in other countries. In addition to preservation efficacy, the compositions will typically exhibit one or more other desirable attributes such as stability, desired pH, clarity, desired osmolality, combinations thereof or the like. The ability to achieve preservation and any other desired attributes is based on a unique combination of formulation ingredients that allow a greater amount of tonicity or osmolality enhancing agent and/or a lower amount of antimicrobial preservative or preservative aid to be present in the composition while still maintaining preservation efficacy.
Ophthalmic compositions that are utilized multiple times by a patient are often referred to as being of a “multi-dose” nature. Such compositions can be manufactured under sterile conditions via procedures that are well known to those skilled in the art. However, once the packaging for a product is opened, such that the composition contained therein is exposed to the atmosphere and other sources of potential microbial contamination (e.g., the hands of a human patient), the sterility of the product may be compromised.
Due to the frequent, repeated exposure of multi-dose products to the risk of microbial contamination, it is necessary to employ a means for preventing such contamination from occurring. The means employed may be: (i) a chemical agent that prevents the proliferation of microbes in a composition, which is referred to herein as an “antimicrobial preservative”; or (ii) a packaging system that prevents or reduces the risk of microbes reaching a pharmaceutical composition within a container.
Prior multi-dose ophthalmic compositions have generally contained one or more antimicrobial preservatives in order to prevent the proliferation of bacteria, fungi and other microbes. Such compositions may come into contact with the cornea either directly or indirectly. The cornea is particularly sensitive to exogenous chemical agents. Consequently, in order to minimize the potential for harmful effects on the cornea, it is preferable to use anti-microbial preservatives that are relatively non-toxic to the cornea, and to use such preservatives at relatively low concentrations.
A desired balance between anti-microbial efficacy and potential toxicological effects of anti-microbial preservatives is often difficult to achieve. More specifically, the concentration of an antimicrobial agent necessary for the preservation of ophthalmic formulations from microbial contamination may create the potential for toxicological effects on the cornea and/or other ophthalmic tissues. Using lower concentrations of the anti-microbial agents generally helps to reduce the potential for such toxicological effects, but the lower concentrations may be insufficient to achieve the required level of biocidal efficacy (i.e., antimicrobial preservation).
The use of an inadequate level of antimicrobial preservation may create the potential for microbial contamination. Such contamination is typically undesirable for most biological systems and particularly undesirable for the human eye.
This balance is further complicated in situations where it is desirable to deliver an anionic therapeutic agent using a multi-dose ophthalmic composition. Preservation agents commonly used for ophthalmic compositions are often positively charged within the composition, particularly when that composition is an aqueous solution. In turn, these agents often interact with anionic drugs in an undesirable manner, which can result in instability of the composition, lack of preservation efficacy, lack of therapeutic efficacy, combinations thereof or the like.
Prior attempts to address these undesirable interactions typically involved the addition of a surfactant to the composition (see U.S. Pat. No. 5,110,493, which is fully incorporated herein by reference for all purposes). However, the addition of surfactant to an ophthalmic composition is often undesirable. Surfactants can add significant expense to the composition. Moreover, as a general rule, it is often undesirable to add further ingredients to an ophthalmic composition where the addition of those ingredients can potentially be avoided.
Thus, there exists a need for ophthalmic compositions that include anionic drugs and still exhibit desirable attributes such as preservation efficacy, stability, desired pH, clarity, desired osmolality, combinations thereof or the like. Moreover, it would be desirable to avoid the use of surfactant or at least lower amounts of surfactant in the composition.